Throughout the globe,diabetes mellitus（DM） is increasing in incidence with limited therapies presently available to prevent or resolve the significant complications of this disorder.DM impacts multiple organs and af...Throughout the globe,diabetes mellitus（DM） is increasing in incidence with limited therapies presently available to prevent or resolve the significant complications of this disorder.DM impacts multiple organs and affects all components of the central and peripheral nervous systems that can range from dementia to diabetic neuropathy.The mechanistic target of rapamycin（m TOR） is a promising agent for the development of novel regenerative strategies for the treatment of DM.m TOR and its related signaling pathways impact multiple metabolic parameters that include cellular metabolic homeostasis,insulin resistance,insulin secretion,stem cell proliferation and differentiation,pancreatic β-cell function,and programmed cell death with apoptosis and autophagy.m TOR is central element for the protein complexes m TOR Complex 1（m TORC1） and m TOR Complex 2（m TORC2） and is a critical component for a number of signaling pathways that involve phosphoinositide 3-kinase（PI 3-K）,protein kinase B（Akt）,AMP activated protein kinase（AMPK）,silent mating type information regulation 2 homolog 1（Saccharomyces cerevisiae）（SIRT1）,Wnt1 inducible signaling pathway protein 1（WISP1）,and growth factors.As a result,m TOR represents an exciting target to offer new clinical avenues for the treatment of DM and the complications of this disease.Future studies directed to elucidate the delicate balance m TOR holds over cellular metabolism and the impact of its broad signaling pathways should foster the translation of these targets into effective clinical regimens for DM.展开更多
Modified constraint-induced movement therapy is an effective treatment for neurological and motor impairments in patients with stroke by increasing the use of their affected limb and limiting the contralateral limb.Ho...Modified constraint-induced movement therapy is an effective treatment for neurological and motor impairments in patients with stroke by increasing the use of their affected limb and limiting the contralateral limb.However,the molecular mechanism underlying its efficacy remains unclear.In this study,a middle cerebral artery occlusion(MCAO)rat model was produced by the suture method.Rats received modified constraint-induced movement therapy 1 hour a day for 14 consecutive days,starting from the 7^th day after middle cerebral artery occlusion.Day 1 of treatment lasted for 10 minutes at 2r/min,day 2 for 20 minutes at 2 r/min,and from day 3 onward for 20 minutes at 4 r/min.CatWalk gait analysis,adhesive removal test,and Y-maze test were used to investigate motor function,sensory function as well as cognitive function in rodent animals from the 1st day before MCAO to the 21^st day after MCAO.On the 21^st day after MCAO,the neurotransmitter receptor-related genes from both contralateral and ipsilateral hippocampi were tested by micro-array and then verified by western blot assay.The glutamate related receptor was shown by transmission electron microscopy and the glutamate content was determined by high-performance liquid chromatography.The results of behavior tests showed that modified constraint-induced movement therapy promoted motor and sensory functional recovery in the middle cerebral artery-occluded rats,but had no effect on cognitive function.The modified constraint-induced movement therapy upregulated the expression of glutamate ionotropic receptor AMPA type subunit 3(Gria3)in the hippocampus and downregulated the expression of the beta3-adrenergic receptor gene Adrb3 and arginine vasopressin receptor 1 A,Avprla in the middle cerebral artery-occluded rats.In the ipsilateral hippocampus,only Adra2 a was downregulated,and there was no significant change in Gria3.Transmission electron microscopy revealed a denser distribution the more distribution of postsynaptic glutamate receptor 2/3,which is an a-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor,within 240 nm of the postsynaptic density in the contralateral cornu ammonis 3 region.The size and distribution of the synaptic vesicles within 100 nm of the presynaptic active zone were unchanged.Western blot analysis showed that modified constraint-induced movement therapy also increased the expression of glutamate receptor 2/3 and brain-derived neurotrophic factor in the hippocampus of rats with middle cerebral artery occlusion,but had no effect on Synapsin I levels.Besides,we also found modified constraint-induced movement therapy effectively reduced glutamate content in the contralateral hippocampus.This study demonstrated that modified constraint-induced movement therapy is an effective rehabilitation therapy in middle cerebral artery-occluded rats,and suggests that these positive effects occur via the upregulation of the postsynaptic membrane a-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor expression.This study was approved by the Institutional Animal Care and Use Committee of Fudan University,China(approval No.201802173 S)on March 3,2018.展开更多
AIM:To study whether immune-activation stage in serum of adult Crohn's disease (CD) patients correlates with disease activity and with treatment response to antitumor necrosis factor-α (TNF-α) therapy.METHODS:Se...AIM:To study whether immune-activation stage in serum of adult Crohn's disease (CD) patients correlates with disease activity and with treatment response to antitumor necrosis factor-α (TNF-α) therapy.METHODS:Serum samples were obtained from 15 adult CD patients introduced to anti-TNF-α therapy.The individual stage of immune activation was studied applying our new in vitro assay,in which target cells (donor derived peripheral blood mononuclear cells) were cultured with patient serum and the T-cell activation induced by the patient serum was studied using a panel of markers for effector [interferon γ (IFNγ),interleukin (IL)-5] and regulatory T-cells [forkhead transcription factor 3 (FOXP3) and glucocorticoid-induced tumour necrosis factor receptor (GITR)].The endoscopic disease activity was assessed with the Crohn's disease endoscopic index of severity (CDEIS) before and 3 mo after therapy with an anti-TNF-α agent.RESULTS:Low induction of FOXP3 and GITR in target cells cultured in the presence of patient serum was associated with high disease activity i.e.CDEIS assessed before therapy (r=-0.621,P=0.013 and r=-0.625,P=0.013,respectively).FOXP3 expression correlated inversely with pre-treatment erythrocyte sedimentation rate (r=-0.548,P=0.034).Low serum induced FOXP3 (r=-0.600,P=0.018) and GITR (r=-0.589,P=0.021) expression and low IFNγ secretion from target cells (r =-0.538,P=0.039) associated with treatment response detected as a decrease in CDEIS.CONCLUSION:The immune-activation potency in the patient serum prior to anti-TNF-α therapy reflected intestinal inflammation and the therapeutic response.展开更多
The mechanism of action of ribavirin(RBV) as an immunomodulatory and antiviral agent and its clinical significance in the future treatment of patients with hepatitis C virus(HCV) infection are reviewed.RBV up-regulate...The mechanism of action of ribavirin(RBV) as an immunomodulatory and antiviral agent and its clinical significance in the future treatment of patients with hepatitis C virus(HCV) infection are reviewed.RBV up-regulates type 1 and/or 2 cytokines to modulate the T helper(Th) 1/2 cell balance to Th1 dominance.Examination of co-stimulatory signaling indicated that RBV down-modulates inducible co-stimulator on Th cells,which contributes to differentiating na?ve Th cells into Th2 cells while reducing their interleukin-10 production.The effects on T-regulatory(Treg) cells were also investigated,and RBV inhibited the differentiation of na?ve Th cells into adaptive Treg cells by downmodulating forkhead box-P3.These findings indicate that RBV mainly down-regulates the activity of Th2 cells,resulting in the maintenance of Th1 activity that contributes to abrogating HCV-infected hepatocytes.Although an interferon-free treatment regimen exhibits almost the same efficacy without serious complications,regimens with RBV will be still be used because of their ability to facilitate the cellular immune response,which may contribute to reducing the development of hepatocellular carcinogenesis in patients infected with HCV.展开更多
AIM To establish a functional and molecular model of the intracellular pH(pH_i) regulatory mechanism in human induced pluripotent stem cells(hiPSCs).METHODS hiP SCs(HPS0077) were kindly provided by Dr. Dai from the Tr...AIM To establish a functional and molecular model of the intracellular pH(pH_i) regulatory mechanism in human induced pluripotent stem cells(hiPSCs).METHODS hiP SCs(HPS0077) were kindly provided by Dr. Dai from the Tri-Service General Hospital(IRB No. B-106-09). Changes in the pH_i were detected either by microspectrofluorimetry or by a multimode reader with a pH-sensitive fluorescent probe, BCECF, and the fluorescent ratio was calibrated by the high K^+/nigericin method. NH_4Cl and Na-acetate prepulse techniques were used to induce rapid intracellular acidosis and alkalization, respectively. The buffering power(β) was calculated from the ΔpH_i induced by perfusing different concentrations of(NH_4)_2SO_4. Western blot techniques and immunocytochemistry staining were used to detect the protein expression of pH_i regulators and pluripotency markers.RESULTS In this study, our results indicated that(1) the steadystate pH_i value was found to be 7.5 ± 0.01(n = 20) and 7.68 ± 0.01(n =20) in HEPES and 5% CO_2/HCO_3^- buffered systems, respectively, which were much greater than that in normal adult cells(7.2);(2) in a CO_2/HCO_3^--buffered system, the values of total intracellular buffering power(β) can be described by the following equation: β_(tot) = 107.79(pH_i)~2-1522.2(pH_i) + 5396.9(correlation coefficient R^2 = 0.85), in the estimated pH_i range of 7.1- 8.0;(3) the Na^+/H^+ exchanger(NHE) and the Na^+/HCO_3^- cotransporter(NBC) were found to be functionally activated for acid extrusion for pHi values less than 7.5 and 7.68, respectively;(4) V-ATPase and some other unknown Na^+-independent acid extruder(s) could only be functionally detected for pHi values less than 7.1;(5) the Cl^-/OH^- exchanger(CHE) and the Cl^- /HCO_3 anion exchanger(AE) were found to be responsible for the weakening of intracellular proton loading;(6) besides the CHE and the AE, a Cl^--independent acid loading mechanism was functionally identified; and(7) in hiPSCs, a strong positive correlation was observed between the loss of pluripotency and the weakening of the intracellular acid extrusion mechanism, which included a decrease in the steady-state pH i value and diminished the functional activity and protein expression of the NHE and the NBC.CONCLUSION For the first time, we established a functional and molecular model of a pHi regulatory mechanism and demonstrated its strong positive correlation with hiPSC pluripotency.展开更多
Microbially induced calcium carbonate precipitation(MICP)is an eco-friendly technology for soil improvement.Although numerous experiments have been conducted to solidify sand foundations using MICP,the mechanisms by w...Microbially induced calcium carbonate precipitation(MICP)is an eco-friendly technology for soil improvement.Although numerous experiments have been conducted to solidify sand foundations using MICP,the mechanisms by which grain interfacial morphologies influencethe MICP process remain unclear.This study utilized 3D-printed flowcells with different boundary morphologies to investigate the effects of interfacial morphologies on the MICP process.CaCO_(3)precipitation characteristics were investigated through microscopic observation and image quantificationanalysis.The results indicate that low flowvelocities near the interface promote bacterial accumulation due to reduced hydrodynamic shear forces.Rough interfaces,compared to smooth ones,enhance bacterial adsorption owing to the larger regions of low flowvelocity,increased surface area,and the formation of local eddies,which promote greater CaCO_(3)precipitation.Compared to the regions away from the interface,a higher abundance of small CaCO_(3)crystals is observed near the interface because of the high urease activity from bacteria and the reduced shear-induced entrainment due to the low flowvelocity.Besides,larger crystals also preferentially precipitate in proximity to interfaces as the low flowvelocity enhances crystal growth according to the particle attachment theory.The presence of rough interfaces further reduces flowvelocities,leading to the precipitation of larger and more densely packed CaCO_(3)crystals.Therefore,rough interfaces promote the microbially induced calcium carbonate precipitation.This work is expected to enhance the understanding of microbially induced calcium carbonate precipitation characteristics on solid surfaces such as soil grains and contribute to the optimization of MICP applications.展开更多
An increasing number of tunnels are being constructed with tunnel-boring machines （TBMs） due to the increased efficiency and shorter completion time resulting from their use. However, when a TBM encoun- ters adverse...An increasing number of tunnels are being constructed with tunnel-boring machines （TBMs） due to the increased efficiency and shorter completion time resulting from their use. However, when a TBM encoun- ters adverse geological conditions in the course of tunnel construction （e.g., karst caves, faults, or frac- tured zones）, disasters such as water and mud inrush, collapse, or machine blockage may result, and may severely imperil construction safety. Therefore, the advance detection of adverse geology and water-bearing conditions in front of the tunnel face is of great importance. This paper uses the TBM tun- neling of the water conveyance project from Songhua River as a case study in order to propose a compre- hensive forward geological prospecting technical system that is suitable for TBM tunnel construction under complicated geological conditions. By combining geological analysis with forward geological prospecting using a three-dimensional （3D） induced polarization method and a 3D seismic method, a comprehensive forward geological prospecting technical system can accurately forecast water inrush geo-hazards or faults in front of the TBM tunnel face. In this way, disasters such as water and mud inrush, collapse, or machine blockage can be avoided. This prospecting technical system also has reference value for carrying out the forward prospecting of adverse geology for potential TBM tunneling and for ensuring that a TBM can work efficiently.展开更多
基金supported by American Diabetes Association,American Heart Association,NIH NIEHS,NIH NIA,NIH NINDS,and NIH ARRA
文摘Throughout the globe,diabetes mellitus（DM） is increasing in incidence with limited therapies presently available to prevent or resolve the significant complications of this disorder.DM impacts multiple organs and affects all components of the central and peripheral nervous systems that can range from dementia to diabetic neuropathy.The mechanistic target of rapamycin（m TOR） is a promising agent for the development of novel regenerative strategies for the treatment of DM.m TOR and its related signaling pathways impact multiple metabolic parameters that include cellular metabolic homeostasis,insulin resistance,insulin secretion,stem cell proliferation and differentiation,pancreatic β-cell function,and programmed cell death with apoptosis and autophagy.m TOR is central element for the protein complexes m TOR Complex 1（m TORC1） and m TOR Complex 2（m TORC2） and is a critical component for a number of signaling pathways that involve phosphoinositide 3-kinase（PI 3-K）,protein kinase B（Akt）,AMP activated protein kinase（AMPK）,silent mating type information regulation 2 homolog 1（Saccharomyces cerevisiae）（SIRT1）,Wnt1 inducible signaling pathway protein 1（WISP1）,and growth factors.As a result,m TOR represents an exciting target to offer new clinical avenues for the treatment of DM and the complications of this disease.Future studies directed to elucidate the delicate balance m TOR holds over cellular metabolism and the impact of its broad signaling pathways should foster the translation of these targets into effective clinical regimens for DM.
基金supported by the National Natural Science Foundation of China,No.81871841(to YLB) and No.81772453(to DSX)
文摘Modified constraint-induced movement therapy is an effective treatment for neurological and motor impairments in patients with stroke by increasing the use of their affected limb and limiting the contralateral limb.However,the molecular mechanism underlying its efficacy remains unclear.In this study,a middle cerebral artery occlusion(MCAO)rat model was produced by the suture method.Rats received modified constraint-induced movement therapy 1 hour a day for 14 consecutive days,starting from the 7^th day after middle cerebral artery occlusion.Day 1 of treatment lasted for 10 minutes at 2r/min,day 2 for 20 minutes at 2 r/min,and from day 3 onward for 20 minutes at 4 r/min.CatWalk gait analysis,adhesive removal test,and Y-maze test were used to investigate motor function,sensory function as well as cognitive function in rodent animals from the 1st day before MCAO to the 21^st day after MCAO.On the 21^st day after MCAO,the neurotransmitter receptor-related genes from both contralateral and ipsilateral hippocampi were tested by micro-array and then verified by western blot assay.The glutamate related receptor was shown by transmission electron microscopy and the glutamate content was determined by high-performance liquid chromatography.The results of behavior tests showed that modified constraint-induced movement therapy promoted motor and sensory functional recovery in the middle cerebral artery-occluded rats,but had no effect on cognitive function.The modified constraint-induced movement therapy upregulated the expression of glutamate ionotropic receptor AMPA type subunit 3(Gria3)in the hippocampus and downregulated the expression of the beta3-adrenergic receptor gene Adrb3 and arginine vasopressin receptor 1 A,Avprla in the middle cerebral artery-occluded rats.In the ipsilateral hippocampus,only Adra2 a was downregulated,and there was no significant change in Gria3.Transmission electron microscopy revealed a denser distribution the more distribution of postsynaptic glutamate receptor 2/3,which is an a-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor,within 240 nm of the postsynaptic density in the contralateral cornu ammonis 3 region.The size and distribution of the synaptic vesicles within 100 nm of the presynaptic active zone were unchanged.Western blot analysis showed that modified constraint-induced movement therapy also increased the expression of glutamate receptor 2/3 and brain-derived neurotrophic factor in the hippocampus of rats with middle cerebral artery occlusion,but had no effect on Synapsin I levels.Besides,we also found modified constraint-induced movement therapy effectively reduced glutamate content in the contralateral hippocampus.This study demonstrated that modified constraint-induced movement therapy is an effective rehabilitation therapy in middle cerebral artery-occluded rats,and suggests that these positive effects occur via the upregulation of the postsynaptic membrane a-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor expression.This study was approved by the Institutional Animal Care and Use Committee of Fudan University,China(approval No.201802173 S)on March 3,2018.
基金Supported by The Finnish Cultural Foundationthe Finnish Pediatric Research Foundation+3 种基金the Pivikki and Sakari Sohlberg Foundationthe Helsinki University Central Hospital Grantthe Orion-Farmos Research Foundationthe Maryand George C Ehrnrooth Foundation
文摘AIM:To study whether immune-activation stage in serum of adult Crohn's disease (CD) patients correlates with disease activity and with treatment response to antitumor necrosis factor-α (TNF-α) therapy.METHODS:Serum samples were obtained from 15 adult CD patients introduced to anti-TNF-α therapy.The individual stage of immune activation was studied applying our new in vitro assay,in which target cells (donor derived peripheral blood mononuclear cells) were cultured with patient serum and the T-cell activation induced by the patient serum was studied using a panel of markers for effector [interferon γ (IFNγ),interleukin (IL)-5] and regulatory T-cells [forkhead transcription factor 3 (FOXP3) and glucocorticoid-induced tumour necrosis factor receptor (GITR)].The endoscopic disease activity was assessed with the Crohn's disease endoscopic index of severity (CDEIS) before and 3 mo after therapy with an anti-TNF-α agent.RESULTS:Low induction of FOXP3 and GITR in target cells cultured in the presence of patient serum was associated with high disease activity i.e.CDEIS assessed before therapy (r=-0.621,P=0.013 and r=-0.625,P=0.013,respectively).FOXP3 expression correlated inversely with pre-treatment erythrocyte sedimentation rate (r=-0.548,P=0.034).Low serum induced FOXP3 (r=-0.600,P=0.018) and GITR (r=-0.589,P=0.021) expression and low IFNγ secretion from target cells (r =-0.538,P=0.039) associated with treatment response detected as a decrease in CDEIS.CONCLUSION:The immune-activation potency in the patient serum prior to anti-TNF-α therapy reflected intestinal inflammation and the therapeutic response.
文摘The mechanism of action of ribavirin(RBV) as an immunomodulatory and antiviral agent and its clinical significance in the future treatment of patients with hepatitis C virus(HCV) infection are reviewed.RBV up-regulates type 1 and/or 2 cytokines to modulate the T helper(Th) 1/2 cell balance to Th1 dominance.Examination of co-stimulatory signaling indicated that RBV down-modulates inducible co-stimulator on Th cells,which contributes to differentiating na?ve Th cells into Th2 cells while reducing their interleukin-10 production.The effects on T-regulatory(Treg) cells were also investigated,and RBV inhibited the differentiation of na?ve Th cells into adaptive Treg cells by downmodulating forkhead box-P3.These findings indicate that RBV mainly down-regulates the activity of Th2 cells,resulting in the maintenance of Th1 activity that contributes to abrogating HCV-infected hepatocytes.Although an interferon-free treatment regimen exhibits almost the same efficacy without serious complications,regimens with RBV will be still be used because of their ability to facilitate the cellular immune response,which may contribute to reducing the development of hepatocellular carcinogenesis in patients infected with HCV.
基金Supported by Ministry of Science and Technology Grants of Taiwan,No.MOST 106-2320-B-016-003-MY2(to Loh SH)and No.MOST 106-2314-B-016-037-MY3(to Tsai YT)National Defense Medical Center Grants of Taiwan,No.MAB-106-033(to Loh SH),No.MAB-105-043 and No.MAB-106-034(to Dai NZ)Teh-Tzer Study Group for Human Medical Research Foundation of Taiwan,No.A1061037 and No.A1061054(to Loh SH)
文摘AIM To establish a functional and molecular model of the intracellular pH(pH_i) regulatory mechanism in human induced pluripotent stem cells(hiPSCs).METHODS hiP SCs(HPS0077) were kindly provided by Dr. Dai from the Tri-Service General Hospital(IRB No. B-106-09). Changes in the pH_i were detected either by microspectrofluorimetry or by a multimode reader with a pH-sensitive fluorescent probe, BCECF, and the fluorescent ratio was calibrated by the high K^+/nigericin method. NH_4Cl and Na-acetate prepulse techniques were used to induce rapid intracellular acidosis and alkalization, respectively. The buffering power(β) was calculated from the ΔpH_i induced by perfusing different concentrations of(NH_4)_2SO_4. Western blot techniques and immunocytochemistry staining were used to detect the protein expression of pH_i regulators and pluripotency markers.RESULTS In this study, our results indicated that(1) the steadystate pH_i value was found to be 7.5 ± 0.01(n = 20) and 7.68 ± 0.01(n =20) in HEPES and 5% CO_2/HCO_3^- buffered systems, respectively, which were much greater than that in normal adult cells(7.2);(2) in a CO_2/HCO_3^--buffered system, the values of total intracellular buffering power(β) can be described by the following equation: β_(tot) = 107.79(pH_i)~2-1522.2(pH_i) + 5396.9(correlation coefficient R^2 = 0.85), in the estimated pH_i range of 7.1- 8.0;(3) the Na^+/H^+ exchanger(NHE) and the Na^+/HCO_3^- cotransporter(NBC) were found to be functionally activated for acid extrusion for pHi values less than 7.5 and 7.68, respectively;(4) V-ATPase and some other unknown Na^+-independent acid extruder(s) could only be functionally detected for pHi values less than 7.1;(5) the Cl^-/OH^- exchanger(CHE) and the Cl^- /HCO_3 anion exchanger(AE) were found to be responsible for the weakening of intracellular proton loading;(6) besides the CHE and the AE, a Cl^--independent acid loading mechanism was functionally identified; and(7) in hiPSCs, a strong positive correlation was observed between the loss of pluripotency and the weakening of the intracellular acid extrusion mechanism, which included a decrease in the steady-state pH i value and diminished the functional activity and protein expression of the NHE and the NBC.CONCLUSION For the first time, we established a functional and molecular model of a pHi regulatory mechanism and demonstrated its strong positive correlation with hiPSC pluripotency.
基金supported by the National Key Research and Development Program of China(Grant No.2023YFC3707900)National Natural Science Foundation of China(Grant No.42230710,42525201)Key task project for joint research and development of the Yangtze River Delta Science and Technology Innovation Community(Grant No.2022CSJGG1200).
文摘Microbially induced calcium carbonate precipitation(MICP)is an eco-friendly technology for soil improvement.Although numerous experiments have been conducted to solidify sand foundations using MICP,the mechanisms by which grain interfacial morphologies influencethe MICP process remain unclear.This study utilized 3D-printed flowcells with different boundary morphologies to investigate the effects of interfacial morphologies on the MICP process.CaCO_(3)precipitation characteristics were investigated through microscopic observation and image quantificationanalysis.The results indicate that low flowvelocities near the interface promote bacterial accumulation due to reduced hydrodynamic shear forces.Rough interfaces,compared to smooth ones,enhance bacterial adsorption owing to the larger regions of low flowvelocity,increased surface area,and the formation of local eddies,which promote greater CaCO_(3)precipitation.Compared to the regions away from the interface,a higher abundance of small CaCO_(3)crystals is observed near the interface because of the high urease activity from bacteria and the reduced shear-induced entrainment due to the low flowvelocity.Besides,larger crystals also preferentially precipitate in proximity to interfaces as the low flowvelocity enhances crystal growth according to the particle attachment theory.The presence of rough interfaces further reduces flowvelocities,leading to the precipitation of larger and more densely packed CaCO_(3)crystals.Therefore,rough interfaces promote the microbially induced calcium carbonate precipitation.This work is expected to enhance the understanding of microbially induced calcium carbonate precipitation characteristics on solid surfaces such as soil grains and contribute to the optimization of MICP applications.
文摘目的明确脓毒症相关脑病(sepsis-associated encephalopathy,SAE)急性期(发病6 h)海马突触损伤的关键分子及其作用机制,阐释脓毒症认知障碍(sepsis-induced cognitive impairment,SICI)的早期神经元损伤途径。方法采用蛋白质组学对脂多糖(lipopolysaccharide,LPS)处理6 h后小鼠海马组织进行差异蛋白筛查并确定候选靶点,在体外构建干扰素诱导蛋白含四肽重复序列3(interferon-induced protein with tetratricopeptide repeats 3,IFIT3)过表达的HT22神经元细胞模型,分为对照组、LPS组、IFIT3过表达组、LPS+IFIT3组、Visomitin预处理组及CY-09共处理组6组。检测线粒体活性氧(mitochondrial reactive oxygen species,mtROS)水平、白细胞介素-1β(IL-1β)释放及突触后致密蛋白95(postsynaptic density protein 95,PSD95)和突触素(synaptophysin,SYN)表达变化。结果LPS处理6 h后小鼠海马中IFIT3表达显著上调。在炎症背景下,IFIT3过表达进一步促进mtROS积累,增强IL-1β释放,并导致PSD95和SYN表达下降。上游清除mtROS的Visomitin能够显著改善突触蛋白丢失,其保护效应优于单纯阻断NOD样受体家族含pyrin结构域蛋白3(NOD-like receptor family pyrin domain containing 3,NLRP3)活化的CY-09。结论IFIT3在炎症背景下参与并放大急性期海马突触损伤过程,其效应与mtROS-NLRP3炎症小体相关级联激活密切相关,提示急诊脓毒症早期脑保护策略中,早期上游靶向mtROS的脑保护策略可能优于单点抑制NLRP3。
文摘An increasing number of tunnels are being constructed with tunnel-boring machines （TBMs） due to the increased efficiency and shorter completion time resulting from their use. However, when a TBM encoun- ters adverse geological conditions in the course of tunnel construction （e.g., karst caves, faults, or frac- tured zones）, disasters such as water and mud inrush, collapse, or machine blockage may result, and may severely imperil construction safety. Therefore, the advance detection of adverse geology and water-bearing conditions in front of the tunnel face is of great importance. This paper uses the TBM tun- neling of the water conveyance project from Songhua River as a case study in order to propose a compre- hensive forward geological prospecting technical system that is suitable for TBM tunnel construction under complicated geological conditions. By combining geological analysis with forward geological prospecting using a three-dimensional （3D） induced polarization method and a 3D seismic method, a comprehensive forward geological prospecting technical system can accurately forecast water inrush geo-hazards or faults in front of the TBM tunnel face. In this way, disasters such as water and mud inrush, collapse, or machine blockage can be avoided. This prospecting technical system also has reference value for carrying out the forward prospecting of adverse geology for potential TBM tunneling and for ensuring that a TBM can work efficiently.
